Immunologic Contributions to the Endometriosis Phenotype

项目总结 子宫内膜异位症，即子宫内膜组织出现在子宫外部位，是一种常见而又神秘的疾病。 影响大约10%-15%育龄妇女生活质量的妇科疾病。 虽然子宫内膜异位症被认为是一种良性疾病，但许多患有这种疾病的妇女都经历了慢性 出现衰弱的疼痛、性交困难、痛经和/或不孕。许多理论都试图 解释疾病的发病机制，包括月经逆行，一种遗传易感性，并改变 非子宫细胞的分化。不幸的是，到目前为止，理论还不能解释所有的疾病发生率。 发生了。因此，我正在探索这样一种可能性，即子宫内膜异位症是一种成人发病的疾病， 导致早期生命内分泌免疫交叉沟通中断。我假设一种宫内毒物 暴露培养骨髓来源的免疫祖细胞(BMDCs)，随后促进 成年期子宫内膜异位症的发展。免疫细胞训练指的是一种记忆的发展 以前的感染，但目前还不清楚免疫细胞是否同样“记得”过去的毒物接触。 然而，我们的实验室已经表明，在子宫内接触TCDD(2，3，7，8-四氯二苯并-对二恶英)在 小鼠导致子宫孕酮(P4)敏感性丧失，并出现炎症反应，这在患有 子宫内膜异位症。在这里，我将利用我们建立的小鼠毒物暴露模型来确定在 子宫TCDD暴露诱导免疫细胞训练促进子宫内膜异位症样子宫的发生 成年小鼠的表型。在特定的目标1中，我将研究毒物介导的腹膜之间的关系 炎症和生殖功能障碍与腹膜免疫表型和子宫的特征 TCDD暴露小鼠与野生型C57/BL6(WT)小鼠的表型比较。此外，我将确定是否 TCDD介导的免疫细胞改变通过过继作用直接导致子宫功能障碍 将TCDD暴露小鼠的BMDCs转移到对照受体小鼠。在具体目标2中，我将阐明 TCDD产生表型的分子机制通过检查表观遗传、代谢和 暴露于TCDD的免疫细胞与未暴露的免疫细胞的功能状态比较。总的来说， 确定免疫细胞对子宫内P4敏感性降低的特定贡献，并确定 靶向通路将决定免疫细胞作为诊断和/或治疗的潜在用途 目标。这项建议建立在我所获得的初步数据的基础上，并将为我提供培训 寻求生殖毒理学、生殖免疫学、免疫毒理学和免疫代谢。搁置一边 通过掌握这些知识和技能，我还将获得必要的数据分析经验， 生成手稿，将我的成果传达给科学和非专业观众，并制定 可检验的假设。在这一奖学金结束时，我将处于攻读博士后的有利地位 在领先的实验室接受培训，并追求成为一名独立调查员的目标。

PROJECT SUMMARY Endometriosis, the presence of endometrial tissue at an extra-uterine site, is a common yet enigmatic gynecologic disease that dampens the quality of life for approximately 10-15% of reproductive-aged women. Although endometriosis is regarded as a benign condition, many women with this disease experience chronic episodes of debilitating pain, dyspareunia, dysmenorrhea, and/or infertility. Numerous theories have attempted to explain disease pathogenesis including retrograde menstruation, a genetic predisposition, and altered differentiation of non-uterine cells. Unfortunately, theories to date have failed to explain all incidences of disease occurrence. Thus, I am exploring the possibility that endometriosis is an adult-onset disease that emerges due to an early life disruption of endocrine-immune cross-communication. I hypothesize that an in utero toxicant exposure trains bone marrow-derived immune progenitor cells (BMDCs) and subsequently promotes the development of endometriosis in adulthood. Immune cell training refers to the development of memory of a previous infection, but it is unknown whether immune cells similarly “remember” a past toxicant exposure. Nevertheless, our laboratory has shown that in utero TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure in mice results in a loss of uterine progesterone (P4) sensitivity and hyperinflammation as seen in women with endometriosis. Herein, I will utilize our established mouse model of toxicant exposure to determine if in utero TCDD exposure induces immune cell training prompting the development of the endometriosis-like uterine phenotype in adult mice. In Specific Aim 1, I will examine the relationship between toxicant-mediated peritoneal inflammation and reproductive dysfunction by characterizing the intraperitoneal immune phenotype and uterine phenotype of TCDD-exposed mice compared to wild-type C57/BL6 (WT) mice. Furthermore, I will determine if TCDD-mediated alterations of immune cells directly contribute to uterine dysfunction by adoptively transferring BMDCs from TCDD-exposed mice to control recipient mice. In Specific Aim 2, I will elucidate the molecular mechanisms underlying the TCDD-generated phenotype by examining the epigenetic, metabolic, and functional status of TCDD-exposed immune cells in comparison to unexposed immune cells. Overall, determining the specific contribution of immune cells to reduced P4 sensitivity within the uterus and identifying targetable pathways will determine the potential utility of immune cells as a diagnostic and/or therapeutic target. This proposal builds upon preliminary data that I have obtained and will provide me with the training I seek in reproductive toxicology, reproductive immunology, immunotoxicology, and immunometabolism. Aside from gaining this knowledge and technical skills, I will also gain necessary experience in data analysis, generation of manuscripts, communication of my results to scientific and lay audiences, and the formulation of testable hypotheses. At the conclusion of this fellowship, I will be well-positioned to undertake postdoctoral training in a leading laboratory and pursue my goal to be an independent investigator.